Reactive gliosis is a neuropathologic hallmark of degenerative diseases such as Alzheimer s disease (AD) and amyotrophic lateral sclerosis (ALS). It is unclear whether the glial reaction contributes to the ongoing neurodegeneration, represents a futile attempt at neuroprotection, or is simply a bystander phenomenon that plays no fundamental neurophysiologic role. Since therapies aimed at modulating glial activation may be effective in slowing the progression of these devastating conditions, it is important to identify the molecular and cellular details underlying chronic gliosis in the CNS. Our laboratory has studied the induction and regulation of a cytosolic, arachidonate-specific phospholipase A2 (cPLA2) in the rat CNS. This enzyme is important in the production of lipid mediators, which subserve inflammatory responses in non-neural tissues, and have been implicated in the response to injury in the CNS as well. We have found that cPLA2 is expressed only at very low levels in normal brain, but is induced in astrocytes found around amyloid plaques in the brains of AD patients, as well as in the brains of transgenic mice which carry a human APP mutation, an animal model of AD. We have also found the lipase is induced in reactive astrocytes in the spinal cord of transgenic animals carrying the human G93A SOD1 mutation, a model for human ALS. Thus, it is our hypothesis that cPLA2 is induced on a chronic basis in Alzheimer s disease and amyotropohic lateral sclerosis, and that it plays a role in the neurodegeneration seen in these diseases. We plan to obtain experimental support for this hypothesis by studying cPLA2 expression in K670N/M671L hAPP transgenic mice, and in the G93A SOD1 mice, and to study how neuropathologic progression is affected by crossing these mice with mice which overexpress cPLA2 constitutively in astrocytes, as well as with mice in cPLA2 has been knocked out by homologous recombination.